TET2 Regulates 5-Hydroxymethylcytosine Signature and CD4⁺ T-Cell Balance in Allergic Rhinitis

Abstract

Purpose Previous studies have shown the role of ten-eleven translocation 2 (TET2) in CD4 + T cells. However, its function in CD4 + T cells under allergic inflammation is unclear. We aimed to investigate the epigenomic distribution of DNA 5-hydroxymethylcytosine (5hmC) and the role of TET2 in CD4 + T cells of allergic rhinitis (AR). Methods The hMeDIP-seq was performed to identify sequences with 5hmC deposition in CD4 + T cells of AR patients. Tet2- deficient or wild type mice were stimulated with ovalbumin (OVA) to develop an AR mouse model. The histopathology in nasal mucosae, Th1/Th2/Treg/Th17 cell percentage, concentrations of Th-related cytokines, expression of Tet and differential hydroxymethylated genes (DhMG), and the global deposition of 5hmC in sorted CD4 + T cells were detected. Results Epigenome-wide 5hmC landscape and DhMG in the CD4 + T cells of AR patients were identified. Tet2 depletion did not led to spontaneous inflammation. However, under the stimulation of allergen, OVA, loss of Tet2 resulted in the exacerbation of allergic inflammation, which was characterized by severer allergic symptoms, more inflammatory cells infiltrating the nasal lamina propria, sharper imbalances between Th1/Th2 and Treg/Th17 cells, and excessive secretion of OVA-specific IgE and Th2-related cytokines. Moreover, altered mRNA production of several DhMG and sharp decrease in 5hmC deposition were also observed in Tet2 -deficient OVA-exposed mice. Conclusions TET2 may regulate DNA 5hmC, DhMG expressions, and CD4 + T cell balance in AR.

Downregulation of TET2 Contributes to Nasal Polypogenesis Through Hypoxia-Inducible Factor 1α-Mediated Epithelial-to-Mesenchymal Transition

“…In the context of airway inflammation, TET2 has been reported to modulate lipid peroxidation and ferroptosis in airway epithelial cells, thereby alleviating inflammation caused by cigarette smoke in chronic obstructive pulmonary disease mice [ 31 ]. Our previous studies have demonstrated that a loss of TET2 results in exacerbated allergic inflammation and an imbalance between Th1/Th2 and Treg/Th17 cells in patients with allergic rhinitis [ 32 , 33 ]. Although TET2 appears to be implicated in the pathogenesis of upper airway inflammation, its precise role in the inflammation initiation and resolution processes of CRSwNP remains to be elucidated.…”

Single molecule DNA methylation and hydroxymethylation reveal unique epigenetic identity profiles of T helper cells

“…Nevertheless, the present study is the first to showcase the specificity and often contrasting 5hmC patterns in a variety of differentiated CD4 + Th subsets. This is an important consideration for studies reporting molecular phenotypes of bulk PBMCs or whole blood 31 . Indeed, these findings also further support the role of 5hmC as a marker of gene activity and Th cell identity.…”